Functional implications of dopamine D1 vs. D2 receptors: A ‘prepare and select’ model of the striatal direct vs. indirect pathways

AbstractThe functions of the D1- and D2-dopamine receptors in the basal ganglia have remained somewhat enigmatic, with a number of competing theories relating to the interactions of the ‘direct’ and ‘indirect pathways’. Computational models have been good at simulating properties of the system, but are typically divorced from the underlying neural architecture. In this article we propose a new model which re-addresses response selection at the level of the basal ganglia. At the core of this response selection system the D1 DA receptor-expressing striatal pathways ‘prepare’ the set of possible appropriate responses. The D2DR-expressing striatal pathways then shape and ‘select’ from this initial response set framework.This article is part of a Special Issue entitled: Ventral Tegmentum & Dopamine

Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory.

RATIONALE: Antenatal exposure to the glucocorticoid dexamethasone dramatically increases the number of mesencephalic dopaminergic neurons in rat offspring. However, the consequences of this expansion in midbrain dopamine (DA) neurons for behavioural processes in adulthood are poorly understood, including working memory that depends on DA transmission in the prefrontal cortex (PFC). OBJECTIVES: We therefore investigated the influence of antenatal glucocorticoid treatment (AGT) on the modulation of spatial working memory by a D1 receptor agonist and on D1 receptor binding and DA content in the PFC and striatum. METHODS: Pregnant rats received AGT on gestational days 16-19 by adding dexamethasone to their drinking water. Male offspring reared to adulthood were trained on a delayed alternation spatial working memory task and administered the partial D1 agonist SKF38393 (0.3-3 mg/kg) by systemic injection. In separate groups of control and AGT animals, D1 receptor binding and DA content were measured post-mortem in the PFC and striatum. RESULTS: SKF38393 impaired spatial working memory performance in control rats but had no effect in AGT rats. D1 binding was significantly reduced in the anterior cingulate cortex, prelimbic cortex, dorsal striatum and ventral pallidum of AGT rats compared with control animals. However, AGT had no significant effect on brain monoamine levels. CONCLUSIONS: These findings demonstrate that D1 receptors in corticostriatal circuitry down-regulate in response to AGT. This compensatory effect in D1 receptors may result from increased DA-ergic tone in AGT rats and underlie the resilience of these animals to the disruptive effects of D1 receptor activation on spatial working memory.The authors’ research is funded by the Wellcome Trust (grant number 086871/Z/08/Z), the MRC (G0701500), a joint award from the MRC (G1000183) and Wellcome Trust (093875/Z/10/ Z) in support of the Behavioral and Clinical Neuroscience Institute at Cambridge University, and an MRC strategic award to the Imperial College-Cambridge University-Manchester University (ICCAM) addiction cluster (G1000018).This is the final version of the article. It first appeared from Springer at http://dx.doi.org/10.1007/s00213-016-4405-8

Atypical action updating in a dynamic environment associated with adolescent obsessive-compulsive disorder

Background: Computational research had determined that adults with obsessive–compulsive disorder (OCD) display heightened action updating in response to noise in the environment and neglect metacognitive information (such as confidence) when making decisions. These features are proposed to underlie patients’ compulsions despite the knowledge they are irrational. Nonetheless, it is unclear whether this extends to adolescents with OCD as research in this population is lacking. Thus, this study aimed to investigate the interplay between action and confidence in adolescents with OCD. Methods: Twenty-seven adolescents with OCD and 46 controls completed a predictive-inference task, designed to probe how subjects’ actions and confidence ratings fluctuate in response to unexpected outcomes. We investigated how subjects update actions in response to prediction errors (indexing mismatches between expectations and outcomes) and used parameters from a Bayesian model to predict how confidence and action evolve over time. Confidence–action association strength was assessed using a regression model. We also investigated the effects of serotonergic medication. Results: Adolescents with OCD showed significantly increased learning rates, particularly following small prediction errors. Results were driven primarily by unmedicated patients. Confidence ratings appeared equivalent between groups, although model-based analysis revealed that patients’ confidence was less affected by prediction errors compared to controls. Patients and controls did not differ in the extent to which they updated actions and confidence in tandem. Conclusions: Adolescents with OCD showed enhanced action adjustments, especially in the face of small prediction errors, consistent with previous research establishing ‘just-right’ compulsions, enhanced error-related negativity, and greater decision uncertainty in paediatric-OCD. These tendencies were ameliorated in patients receiving serotonergic medication, emphasising the importance of early intervention in preventing disorder-related cognitive deficits. Confidence ratings were equivalent between young patients and controls, mirroring findings in adult OCD research

Building a Better Racetrack

We find IIb compactifications on Calabi-Yau orientifolds in which all Kahler moduli are stabilized, along lines suggested by Kachru, Kallosh, Linde and Trivedi.Comment: 47 pages, 1 figure, harvmac (v2: added references, minor comments, v3: improved discussion of metastability and explicit flux vacua

Altered subcortical emotional salience processing differentiates Parkinson’s patients with and without psychotic symptoms

Objective Current research does not provide a clear explanation for why some patients with Parkinson’s Disease (PD) develop psychotic symptoms. The ‘aberrant salience hypothesis’ of psychosis has been influential and proposes that dopaminergic dysregulation leads to inappropriate attribution of salience to irrelevant/non-informative stimuli, facilitating the formation of hallucinations and delusions. The aim of this study is to investigate whether non-motivational salience is altered in PD patients and possibly linked to the development of psychotic symptoms. Methods We investigated salience processing in 14 PD patients with psychotic symptoms, 23 PD patients without psychotic symptoms and 19 healthy controls. All patients were on dopaminergic medication for their PD. We examined emotional salience using a visual oddball fMRI paradigm that has been used to investigate early stages of schizophrenia spectrum psychosis, controlling for resting cerebral blood flow as assessed with arterial spin labelling fMRI. Results We found significant differences between patient groups in brain responses to emotional salience. PD patients with psychotic symptoms had enhanced brain responses in the striatum, dopaminergic midbrain, hippocampus and amygdala compared to patients without psychotic symptoms. PD patients with psychotic symptoms showed significant correlations between the levels of dopaminergic drugs they were taking and BOLD signalling, as well as psychotic symptom scores. Conclusion Our study suggests that enhanced signalling in the striatum, dopaminergic midbrain, the hippocampus and amygdala is associated with the development of psychotic symptoms in PD, in line with that proposed in the ‘aberrant salience hypothesis’ of psychosis in schizophrenia

Wetting films on chemically heterogeneous substrates

Based on a microscopic density functional theory we investigate the morphology of thin liquidlike wetting films adsorbed on substrates endowed with well-defined chemical heterogeneities. As paradigmatic cases we focus on a single chemical step and on a single stripe. In view of applications in microfluidics the accuracy of guiding liquids by chemical microchannels is discussed. Finally we give a general prescription of how to investigate theoretically the wetting properties of substrates with arbitrary chemical structures.Comment: 56 pages, RevTeX, 20 Figure

Spatializing the Ecological Leviathan: Territorial Strategies and the Production of Regional Natures

This paper explores a dual absence – the absence of the state within contemporary geographical analyses of nature; and the absence of nature within contemporary explorations of state power. We argue that the modern state continues to play a crucial role in framing social interactions with nature, while nature is still vital to states within their realization of different forms of material and ideological power. In order to reconnect analyses of the state and nature, this paper combines work on the production of nature and state strategy with Lefebvre’s recently translated writings on state space and territory. By focusing on the production of territory (or state space), we explore the interaction of the state and nature in the context of the political management of social and ecological space. We unravel the spatial entanglements of the state and nature through an analysis of the British state’s territorial strategies within the West Midlands region. By considering three key historical periods within the history of the West Mid-lands we reveal how the emergence of the regional space called the West Midlands is a product of the ongoing spatial dialectics of state and nature therein